X‐linked hypophosphataemia: A homologous phenotype in humans and mice with unusual organ‐specific gene dosage

Abstract

XLH (X-linked hypophosphataemia, gene symbol HYP, McKusick 307800, 307810) and its murine counterparts (Hyp and Gy) map to a conserved segment on the X-chromosome (Xp 22.31-p.21.3, human; distal X, mouse). Gene dosage has received relatively little attention in the long history of research on this disease, which began over 50 years ago. Bone and teeth are sites of the principal disease manifestations in XLH (rickets, osteomalacia, interglobular dentin). Newer measures of quantitative XLH phenotypes reveal gene dose effects in bone and teeth with heterozygous values distributed between those in mutant hemizygotes and normal homozygotes. On the other hand, serum phosphate concentrations (which are low in the mutant phenotype and thereby contribute to bone and tooth phenotypes) do not show gene dosage. In Hyp mice serum values in mutant hemizygotes, mutant homozygotes and heterozygotes are similar. Phosphate homeostasis reflects its renal conservation. Renal absorption of phosphate on a high-affinity, Na+ ion-gradient coupled system in renal brush border membrane is impaired and gene dosage is absent at this level; the mutant phenotype is fully dominant. Synthesis and degradation of 1,25(OH)2D are also abnormal in XLH (and Hyp), but gene dosage in these parameters has not yet been measured. An (unidentified) inhibitory trans-acting product of the X-linked locus, affecting phosphate transport and vitamin D metabolism, acting perhaps through cytosolic protein kinase C, could explain the renal phenotype. But why would it have a normal gene dose effect in bone and teeth? Since the locus may have duplicated (to form Hyp and Gy), and shows evidence of variable expression in different organs (inner ear, bone/teeth, kidney), it may have been recruited during evolution to multiple functions.

Partial Rescue of theHypPhenotype by Osteoblast-TargetedPHEX(Phosphate-Regulating Gene with Homologies to Endopeptidases on the X Chromosome) Expression

“…It is characterized by severe hypophosphatemia arising from a defect in the renal reabsorption of filtered Pi, inappropriately normal serum levels of 1,25-dihydroxyvitamin D 3 [1, 2 D 3 ] for the degree of hypophosphatemia, and abnormalities in bone and tooth development leading to clinical, radiological, and histomorphometric evidence of rickets, osteomalacia, and dentin defects (1). Established therapy by oral Pi and 1,25-(OH) 2 D 3 administration is less than ideal.…”

A Clinical and Molecular Genetic Study of Hypophosphatemic Rickets in Children

“…For phenotypic analysis, the severities of the two principal disease manifestations, i.e. skeletal or dental diseases were determined (3,19) and initial laboratory data were obtained. Skeletal disease was graded as "mild" or "severe" based on the need for orthopedic surgery.…”

Oncogenic osteomalacia: is there a new phosphate regulating hormone?

“…The lack of a gene dose effect in Hyp mice (Qiu et al, 1993) is also consistent with a humoral factor. In HYP patients there is evidence for a gene dose effect in mineralization of bone and teeth, although there are no differences between males and females in renal phosphate handling (Scriver & Tenenhouse, 1992). The recent demonstration of inhibition by Hyp mouse serum of phosphate uptake by primary mouse proximal tubular cells also provides evidence for a circulating phosphaturic factor in Hyp, a factor which may be produced in part by osteoblasts (Lajeunesse et al, 1996).…”